Roles of FGF2 and TGFbeta1 in cardiac hypertrophy. Cardiac hypertrophy is thought to be an adaptive response to multiple stresses on the heart, such as mechanical load, hypertension, endocrine imbalance and mutations in sarcomeric proteins, which initially increase cardiac output, but eventually lead to heart failure. Increased cardiomyocyte size, synthesis and organization of sarcomeric proteins, increased expression of fetal cardiac genes, and induction of immediate-early genes are all characteristics of cardiac hypertrophy. Many extrinsic factors such as vasoactive peptides, IL6 family cytokines, adrenergic agonists and mechanical stretch have been shown to stimulate cardiac hypertrophy. Recently, we have shown that two mouse strains deficient for the Fibroblast Growth Factor-2 (Fgf2) and Transforming Growth Factor beta-1 (Tgfb1) genes do not respond to the hypertrophic stimuli of pressure overload or subpressor doses of angiotensin II, respectively, demonstrating that these two growth factors play essential roles in cardiac hypertrophy. Surprisingly, neither the absence of growth factor nor the absence of hypertrophy necessarily correlated with increased expression of fetal cardiac genes, which is thought to be a characteristic of cardiac hypertrophy. An understanding of the signaling pathways by which these two growth factors mediate cardiac hypertrophy would be quite useful for designing therapeutic protocols around specific signaling molecules or pathways. But since both growth factors can signal through multiple pathways, many of which, such as MAP kinase and calcineurin pathways, have been implicated in cardiac hypertrophy, it will first be necessary to determine which pathway(s) are utilized by these two growth factors under different stimuli. To this end we propose to apply pressure overload and angiotensin II treatment to both Fgf2 and Tgfb1 knockout mice and then analyze the differential signaling pathways activated in the presence and absence of each growth factor. For each growth factor the pathways that correlate with hypertrophy, pressure overload, activation of the renin angiotensin system, or upregulation of fetal cardiac genes will be assessed.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070174-02
Application #
6623478
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Buxton, Denis B
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$379,217
Indirect Cost
Name
University of Cincinnati
Department
Genetics
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Nusayr, Eyad; Sadideen, Doraid Tarek; Doetschman, Tom (2013) FGF2 modulates cardiac remodeling in an isoform- and sex-specific manner. Physiol Rep 1:
Nusayr, Eyad; Doetschman, Tom (2013) Cardiac development and physiology are modulated by FGF2 in an isoform- and sex-specific manner. Physiol Rep 1:
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Conway, Simon J; Doetschman, Thomas; Azhar, Mohamad (2011) The inter-relationship of periostin, TGF beta, and BMP in heart valve development and valvular heart diseases. ScientificWorldJournal 11:1509-24
Nakao, Shintaro; Maruyama, Kazuichi; Zandi, Souska et al. (2010) Lymphangiogenesis and angiogenesis: concurrence and/or dependence? Studies in inbred mouse strains. FASEB J 24:504-13
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Liao, Siyun; Bodmer, Janet R; Azhar, Mohamad et al. (2010) The influence of FGF2 high molecular weight (HMW) isoforms in the development of cardiac ischemia-reperfusion injury. J Mol Cell Cardiol 48:1245-54

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